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Drug Design, Development and Therapy Volume 10, 2016 - Issue
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Original Research

Flurbiprofen–antioxidant mutual prodrugs as safer nonsteroidal anti-inflammatory drugs: synthesis, pharmacological investigation, and computational molecular modeling

Zaman Ashraf1 Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan;2 Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea
,
Alamgeer3 Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan
,
Munazza Kanwal1 Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan
,
Mubashir Hassan2 Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of Korea
,
Sahar Abdullah3 Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan
,
Mamuna Waheed3 Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan
,
Haseeb Ahsan3 Department of Pharmacology, Faculty of Pharmacy, University of Sargodha, Sargodha, Pakistan
&
Song Ja Kim2 Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, Republic of KoreaCorrespondence[email protected]
 show all
Pages 2401-2419 | Published online: 27 Jul 2016

Figures & data

Figure 1 Synthesis of flurbiprofen–antioxidant mutual prodrugs.

Notes: (1) is starting material; (2) is intermediate which is used in the next step for the synthesis of final prodrugs.
Abbreviation: DMF, dimethylformamide.
Figure 1 Synthesis of flurbiprofen–antioxidant mutual prodrugs.

Figure 2 In vitro hydrolytic pattern of the ester prodrugs (4a–d) in SIF (pH 7.4).

Abbreviation: SIF, simulated intestinal fluid.
Figure 2 In vitro hydrolytic pattern of the ester prodrugs (4a–d) in SIF (pH 7.4).

Figure 3 In vitro hydrolytic pattern of the ester prodrugs (4a–d) in 80% human plasma (pH 7.4).

Figure 3 In vitro hydrolytic pattern of the ester prodrugs (4a–d) in 80% human plasma (pH 7.4).

Table 1 Determination of anti-inflammatory activity of different derivatives of flurbiprofen by the carrageenan hind paw edema method

Table 2 Determination of anti-inflammatory activity of different derivatives of flurbiprofen by egg albumin-induced paw edema in mice

Table 3 Determination of the analgesic activity of derivatives of flurbiprofen by the acetic acid-induced writhing method in mice

Table 4 Determination of analgesic activity of selective flurbiprofen derivatives by the formalin-induced paw licking method in mice

Table 5 Effect of test compounds against brewer’s yeast-induced pyrexia in mice

Table 6 Ulcerogenic activity of synthesized prodrugs (4a–d) and flurbiprofen

Table 7 Chemoinformatics and molecular properties of ligand molecules

Table 8 COX-1 and COX-2 docking energy values

Figure 4 Binding interaction of COX-1 against five different inhibitors.

Notes: A predicted 3D crystal of COX-1 is highlighted in the center with green and light blue color. Five different (protein–ligands) complexes are shown in circles. All the ligand molecules are shown in dark gray color and functional group is shown in red color. The interacting residues are highlighted in wire form. The hydrogen binding distance is represented in dotted lines with binding distance in angstrom (Å).
Abbreviation: COX-1, cyclooxygenase 1.
Figure 4 Binding interaction of COX-1 against five different inhibitors.

Figure 5 Binding interaction of COX-2 against five different inhibitors.

Notes: A predicted 3D crystal of COX-2 is shown in the center with green and gray color. Five different (protein–ligands) complexes are shown in circles. All the ligand molecules are shown in dark gray color and functional group is shown in red color. The interacting residues are highlighted in wire form. The hydrogen binding distance is represented in dotted lines with binding distance in angstrom (Å).
Abbreviation: COX-2, cyclooxygenase 2.
Figure 5 Binding interaction of COX-2 against five different inhibitors.

Figure 6 RMSD graph of COX-1 and COX-2 proteins at different time scales from 0 ps to 10,000 ps.

Abbreviations: COX, cyclooxygenase; RMSD, root mean square deviation.
Figure 6 RMSD graph of COX-1 and COX-2 proteins at different time scales from 0 ps to 10,000 ps.

Figure 7 RMSF graph of COX-1 and COX-2 at different time scales from 0 ps to 10,000 ps.

Abbreviations: COX, cyclooxygenase; RMSF, root mean square fluctuation.
Figure 7 RMSF graph of COX-1 and COX-2 at different time scales from 0 ps to 10,000 ps.

Figure 8 Rg graph of COX-1 and COX-2 at different time scales from 0 ps to 10,000 ps.

Abbreviations: COX, cyclooxygenase; Rg, radius of gyration.
Figure 8 Rg graph of COX-1 and COX-2 at different time scales from 0 ps to 10,000 ps.

Figure 9 Solvent accessible surface area graph of COX-1 and COX-2 at different time scales from 0 ps to 10,000 ps.

Abbreviation: COX, cyclooxygenase.
Figure 9 Solvent accessible surface area graph of COX-1 and COX-2 at different time scales from 0 ps to 10,000 ps.

Figure S1 Superimposed structures of COX-1 and COX-2 with binding pocket.

Abbreviation: COX, cyclooxygenase.
Figure S1 Superimposed structures of COX-1 and COX-2 with binding pocket.

Figure S2 The hydrophobic graphs for predicted model of COX-1, having row index (number of residues) at x-axis and hydrophobic value at y-axis.

Note: The blue lines show the hydrophobic intensity of COX-1.
Abbreviation: COX, cyclooxygenase.
Figure S2 The hydrophobic graphs for predicted model of COX-1, having row index (number of residues) at x-axis and hydrophobic value at y-axis.

Figure S3 The hydrophobic graphs for predicted model of COX-2, having row index (number of residues) at x-axis and hydrophobic value at y-axis.

Note: The blue lines show the hydrophobic intensity of COX-2.
Abbreviation: COX, cyclooxygenase.
Figure S3 The hydrophobic graphs for predicted model of COX-2, having row index (number of residues) at x-axis and hydrophobic value at y-axis.

Figure S4 Ramachandran plot of COX-1.

Notes: 90.7% (486/536) of all residues were in favored (98%) regions; 97.4% (522/536) of all residues were in allowed (>99.8%) regions.
Abbreviation: COX, cyclooxygenase.
Figure S4 Ramachandran plot of COX-1.

Figure S5 Ramachandran plot of COX-2.

Notes: 94.7% (1,042/1,100) of all residues were in favored (98%) regions; 99.9% (1,099/1,100) of all residues were in allowed (>99.8%) regions.
Abbreviation: COX, cyclooxygenase.
Figure S5 Ramachandran plot of COX-2.

Table S1 The clinical effects on animals during the experiments

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